CHEM 445 / BIOL 445
Biochemistry II

J. D. Cronk
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Lecture 27. Amino acid catabolism

Monday 2 April 2007

The catabolic classes and integration of amino acid catabolism. Branched-chain amino acid catabolism. Aromatic amino acid degradation. Monooxygenases and the biopterin cofactor. Dioxygenases. Inborn errors of amino acid metabolism.

Reading: BTS6, Ch.23, pp.666-676.

 
27. Summary

Lecture 27 Summary

Amino acids can be classed according to whether their catabolites can be used (in humans and other animals) as inputs for gluconeogenesis, or if they can only yield the equivalent of acetyl CoA. In the former case, the amino acid is said to be glucogenic, while in the latter case the term ketogenic is used. A number of amino acids are both glucogenic and ketogenic. In fact, there are only two amino acids that are strictly ketogenic - leucine and lysine. Because pyruvate and citric acid cycle intermediates can be converted into glucose, amino acids catabolized to these molecules are glucogenic. When acetyl CoA and/or acetoacetate are produced by the breakdown of an amino acid, it is ketogenic. The amino acids are organized below in a Table of Catabolic Classes.

The transamination of alanine leads straightaway to pyruvate. The transformation of serine to pyruvate can be understood as a PLP-facilitated b-elimination (dehydration) by the enzyme serine dehydratase, followed by non-enzymatic hydrolysis of the resulting (unstable) aminoacrylate. PLP-mediated displacement of the b-substituent interconverts cysteine and serine.

Diagram of reactions and enzyme names for glycine cleavage system and the PLP-dependent glycine hydroxymethyltransferase

   Glycine is metabolized by the combination of a glycine cleavage system and the PLP-dependent enzyme glycine hydroxymethyltransferase (EC 2.1.2.1 - also known as serine hydroxymethyltransferase). These enzymes are linked by one-carbon transfer via the tetrahydrofolate (THF) cofactor. The glycine cleavage system carries out an oxidative fragmentation of glycine by means of a multienzyme complex. The alpha carbon fragment is acquired by THF in a form equivalent to the aldehyde level of oxidation. This fragment in turn adds to another glycine molecule in the glycine hydroxymethyltransferase reaction.  

Inborn errors of metabolism

The catabolic pathways of the aromatic amino acids, Phe, Tyr, and Trp are more complex than those of most other amino acids, and are distingished by the requirement to break apart aromatic rings. This is facilitated by oxidative reactions, i.e. hydroxylation of the ring.

One of the most well-known diseases caused by an inherited defect in metabolism, phenylketonuria (PKU, described below), is associated with the lack of ability to catabolize phenylalanine.

Phenylalanine hydroxylase (PAH) and the tetrahydrobiopterin (BH4) cofatcor

The first step in Phe catabolism is catalyzed by phenylalanine hydroxylase (PAH - EC 1.14.16.1). PAH is an example of a broad classs of enzymes called monooxygenases. These enzymes use molecular oxygen, incorporating one of its oxygen atoms in the substrate being oxidized, while the other oxygen atom shows up in the form of water, via an enzyme cofactor. PAH attaches one oxygen atom to the phenyl ring of phenylalanine yielding tyrosine. The cofactor in PAH that accepts an oxygen is tetrahydrobiopterin (BH4), which is related to the tetrahydrofolate (THF) cofactor.

Diagram of cycle of reactions associated with aromatic amino acid hydroxylation, regeneration of BH4 cofactor

   The figure at left shows the reactions associated with Phe hydroxylation, catalyzed by a system of three seperate enzymes. Hyperphenylalanenemia and phenyketonuria (PKU): An elevated level of phenylalanine in the blood is known as hyperphenylalanenemia. Severe hyperphenylalanenemia is often associated with defective PAH (see p.655, BTS), and this underlies classic phenylketonuria, or PKU I. An alternative form of PKU - PKU II - occurs due to mutation in dihydropteridine reductase (EC 1.5.1.34).

Catabolic classes of amino acids

Amino acids can be classed according to whether their catabolites are glucogenic or ketogenic. A number of amino acids are both glucogenic and ketogenic. In fact, there are only two amino acids that are strictly ketogenic - leucine and lysine. (Here the links to the amino acid names - and in the table below - will open a window showing details of the degradation of that amino acid.) Because pyruvate and citric acid cycle intermediates can be converted into glucose, amino acids catabolized to these molecules are glucogenic. When acetyl CoA and/or acetoacetate are produced by the breakdown of an amino acid, it is ketogenic.
 

Table: Catabolic classes of the 20 standard amino acids

Amino acid General class Catabolic product(s) Notes
Alanine glucogenic pyruvate via transamination
Arginine glucogenic a-ketoglutarate urea cycle intermediate
Asparagine glucogenic oxaloacetate or fumarate asparaginase yields aspartate + ammonia
Aspartate glucogenic oxaloacetate or fumarate via transamination or urea cycle
Cysteine glucogenic pyruvate sulfur can appear as H2S, SO32-, or SCN-
Glutamate glucogenic a-ketoglutarate via transamination
Glutamine glucogenic a-ketoglutarate glutaminase yields glutamate + ammonia
Glycine glucogenic pyruvate via serine
Histidine glucogenic a-ketoglutarate via glutamate
Isoleucine glucogenic & ketogenic succinyl CoA, acetyl CoA branched-chain a-keto acid dehydrogenase
Leucine ketogenic acetyl CoA, acetoacetate  
Lysine ketogenic acetyl CoA, acetoacetate side chain similar to fatty acid chain
Methionine glucogenic succinyl CoA, cysteine Met can yield pyruvate via Cys catabolism
Phenylalanine glucogenic & ketogenic fumarate, acetoacetate First converted to tyrosine
Proline glucogenic a-ketoglutarate via glutamate
Serine glucogenic pyruvate via direct deamination of aminoacrylate
Threonine glucogenic & ketogenic pyruvate, acetyl CoA 2 paths both yield acetyl CoA + glycine
Tryptophan glucogenic & ketogenic pyruvate, acetoacetate  
Tyrosine glucogenic & ketogenic fumarate, acetoacetate  
Valine glucogenic succinyl CoA branched-chain a-keto acid dehydrogenase

Study questions

  • Distinguish between glucogenic and ketogenic. Are these mutually exclusive terms?
  • Predict which genetic defect is likely to be more severe: Loss of phenylalanine hydroxylase activity or loss of dihydropteridine reductase activity. Explain. Does your prediction agree with information available at OMIM?

Page updated 01-01-07

References

1. Berg, Tymoczko, and Stryer. Biochemistry (BTS): 6th edition (2007, Freeman) Ch.23, pp.666-676.
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